PROJECT IV: Pathologic Alpha-synuclein Strains & Diverse Synucleinopathies Project IV Leader: J.Q. Trojanowski; Co-Investigators: V.M.-Y. Lee & K. Luk Project IV Summary/Abstract Here we test the hypothesis that progression of alpha-synuclein (a-syn) pathology in Parkinson's disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB) represent the spread of different a- syn strains in neurons where they are known as Lewy bodies (LBs) and neurites (LNs). We compare these strains to each other and with a-syn strains in multiple system atrophy (MSA) glial cytoplasmic inclusions (GCI). This will advance insights into how distinct a-syn strains drive clinical and pathological heterogeneity in these diverse synucleinopathies. Since dementia in PDD and DLB frequently is accompanied by Alzheimer's disease (AD), we also will test the hypothesis that a-syn strains from PD/PDD/DLB brains (designated LB-a- syn) induce A? and tau pathologies compared to pathological a-syn from MSA brains (designated GCI-a-syn). Project IV collaborates with Project III, which performs in vitro a-syn strain studies and provides Project IV with a-syn strains from postmortem PD/PDD/ DLB and MSA brains as well as in vitro amplified LB and GCI a-syn strains. Living subjects are studied in Core B and Projects I/II and their brains are obtained through Core C while Core D provides data management/biostatistics/bioinformatics support. Thus, Project IV works closely with all Udall Center Cores/Projects to determine if LB-a-syn and GCI-a-syn strains differentially induce pathological a-syn in neurons versus glia as well as recruit AD-like plaque and tangle pathology, This will be done following intracerebral injections into wild type (WT) mice, human WT a-syn transgenic (Tg) mice (line 61) in a mouse a-syn knock out (KO) background (KO61) and CNP-a-syn (M2) Tg mice in a-syn KO background (KOM2) that model GCIs versus Tg mouse models of A? (5xFAD, Tg2576, APP knock in) or tau (PS19) pathologies. The hypothesis tested in Project IV emerged from studies in this funding cycle using synthetic a- syn preformed fibrils, and we innovate now by using LB-a-syn and GCI-a-syn after showing that they are biologically distinct a-syn strains with GCI-a-Syn being ~1000 fold more potent than LB-a-syn. Hence, we test the novel hypothesis that PD/PDD/DLB versus MSA result from different a-syn strains.